Unsaturated aldehydes and process for the preparation of such compounds



United States Patent UNSATURATED ALDEHYDES AND PROCESS FOR THEPREPARATION OF SUCH COMPOUNDS Otto Isler, Marc Montavon, and RudolfRiiegg, Basel, and Paul Zeller, Neuallschwil, Switzerland, assignors toHoifmanu-La Roche Inc., Nutley, N. J., a corpora tion of New Jersey 1 NoDrawin Application August 10, 1955 Serial No. 527,644

Claims priority, application Switzerland August 16, 1954 12 Claims. (Cl.260-488) analogous compounds unsaturated in the 2,3-position isconverted into the enolester and the latter hydrolyzed under mildconditions.

The starting materials of the process can be prepared as follows:

2,6,6-TRIMETHYLCYCLOHEXYLIDENE ACETAL- DEHYDE (ISO-C -ALDEHYDE) Theethoxyacetylene carbinol obtained by the condensation of ethoxyacetylenewith 2,6,6-trimethylcyclohexanone-(l) is partially hydrogenated in theknown manner at the triple bond and treated with acid; colorless oil; B.P. =l10 C.; 11 =1.496; ultraviolet maximum: 237-238 m (in petroleumether) (see copending application Ser. No. 479,217, filed December 31,1954, now Patent No. 2,798,095).

2,6,6 TRIMETHYLCYCLOHEXEN (2) YLIDENE- ACETALDEHYDE (RETRODEHYDRO-CALDE- HYDE) The ethoxyacetylene carbinol obtained by condensa-.

tion of ethoxyace'tylene and 2,6,G-trimethylcyclohexen- (2)-one-(1) ispartially hydrogenated in the known manner at the triple bond andtreated with acid; yellowish oil; B. P. =1l5 C.; n =l.531; ultravioletmaximum:

278 mg (in petroleum-ether solution) (see copending application Ser. No.479,217, filed December 31, 1954).

4 [2',6,6' TRIMETHYLCYCLOHEXYLIDENEl- 2 METHYL BUTEN (2) AL .(1) (ISO CALDEHYDE) The aforementioned iso-C -a'ldehyde is acetalized, the acetalobtained is condensed with a propenylether in the presence of an acidcondensation agent, and the condensation product formed is, treated withacid (see copending application Ser. No. 527,643, filed August 10,1955).

The iso-C -aldehyde can also be obtained by condensing2,6,6-trimethylcyclohexanone-(l) by a Grignard reaction withZ-methyl-1-methoxy-2-oxy-butine-(3), partially hydrogenating at thetriple bond the acetyleneglycol obtained and dehydrating .theethylene'glycol formed and treating it with acid.

Yellowish oil; B. P. =82 to 84 C.; ultraviolet maximum: 288 me (inpetroleum-ether solution).

4 [2',6',6' TRIMETHYLCYCLOHEXEN (2) YLIDENE]v 2 METHYL BUTEN (2) L "(1)(RETRODEHYDROCH-ALDEHYDE) 2,874,183 Patented Feb. 17, 1959 The abovementioned retrodehydro-C -aldehyde is acetalized, the acetal obtained iscondensed with a propenylether in the presence of an acid condensationagent,

The retrodehydro-C -aldehyde can also be obtained by condensingfi-ionone by a glycide ester reaction with ethylchloro-acetate,subjecting the glycide ester obtained to alkaline saponification,brominating the 4-[2',6,6-trimethylcyclohexen (1') yl] 2 methyl buten(2)- al-(l) with N-bromosuccinimide and splitting oif hydrogen bromidefrom the bromination product obtained by means of quinoline. Yellow oil;B. P. =94 C.; n 1.610; ultraviolet maximum: 318 mu (in petroleumethersolution).

In the first step ofthe process in accordance with the invention, theinitial aldehyde is converted into an enolester. This is done in a knownmanner. For instance, the starting material can be treated with loweraliphatic carboxylic acid anhydrides in the presence of acidcondensation agents such as p-toluenesulfonic acid, zinc chloride, etc.,or of alkalior alkali-earth salts of the corresponding acids. Theinitial aldehyde can also be treated in the presence of acidcondensation agents with an enolester of a ketone having a lower boilingpoint than the initial aldehyde, in which connection, by the continuousremoval of the ketone from the reaction mixture, the enolester of theinitial aldehyde is produced. In the preferred embodiment of theinvention, the iso-C or retrodehydro-C or iso-C or retrodehydro-C -alderhyde respectively is heated with acetic anhydride in the presence ofp-toluenesulfonic acid or sodium acetate, or is heated at to C. withisopropenylacetate in the presence of p-toluenesulfonic acid,continuously distilling ofi the acetone which is released. In thismanner there is obtained substantially pure enolesters in almostquantitative yield in the form of colorless to yellowish oils which showcharacteristic absorption maxima in the ultraviolet spectrum. For thefurther use, a special purification, for instance by distillation, isnot necessary.

The second step of the process in accordance with the invention consistsin hydrolyzing the enolesters of the initial aldehydes under mildconditions. This is done in the known manner in an aqueous medium. Forthis purpose there are particularly well suited the alkali andalkaliearth hydroxides, -carbonates or -bicarbonates. A watermisciblesolvent such as methyl alcohol, ethyl alcohol, dioxane, etc., can beadded to the reaction mixture in order to obtain a homogeneous reactionmixture. enolesters are preferably boiled for 10 to 15 hours with sodiumbicarbonate in 90% aqueous methyl alcohol.

The aldehydes obtained in accordance with the present process aredistillable oils which have characteristic absorption maxima in theultraviolet spectrum.

v PHE NYLSEMICARBAZONES OF THE ALDEHYDES Ultraviolet absorption maximain petroleurm Melting ether solution point, 0

Milli- E} microns fl-cn-aldehydennr 157-159 248 805fl-dehydro-Ou-aldehyde 158-160 248 712 B-OH-aldehyde 178-179 237; 276000; 1,065

B-dehydro'Cn-aldehyde 180-192 236; 282 635; 1,170

The B-C -aldehyde and the fi-C -aldehyde are valuable intermediates forthe synthesis of vitamin A and B-carotene. The fi-dehydro-C -aldehydeand the ,S-dehydro-C -aldehyde are intermediates for the synthesis ofVitamin A; and of carotenoids (see copending applica- The tion Ser. No.553,214, filed-December 15, 1955 and now abandoned).

Example 1 ENOLACETATE OF ISO-Cu-ALDEHYDE 50 parts by Weight of2,6,6-trimethylcyclohexylideneacetaldehyde are boiled for 2 hours underreflux with 150 parts by volume acetic anhydride and 30parts by weightfused sodium acetate. The reaction solution is then poured into amixture of 200 parts by weight of ice and 200 parts by volume of Water,extracted with petroleum-ether, whereupon the petroleum-ether solutionis washed with water and dried over sodium sulfate. After the solventhas been evaporated otf, the residue is distilled in vacuum. There areobtained 55 parts by weight2-[2,6',6'-trimethylcyclohexen-(1')-yl]-1'acetoxyethylene. B. P. =ll5 to120 C.; n =1.486; ultraviolet absorption maximum at 232 mu;

Ei=320 (in petroleum-ether solution).

B-Ci1-ALDEHYDE To 55 parts by weight 2-[2,6',6'-trimethylcyclohexen-(1')-yl]-1-acetoxy-ethylene, there are added 300 parts by volume methylalcohol, 30 parts by volume of water and 23 parts by weight sodiumbicarbonate and the reaction mixture is heated for hours under refluxwith agitation. Thereupon it is diluted with 700 parts by volume oficewater and slightly acidified with dilute sulfuric acid. The reactionproduct is extracted with petroleum-ether, washed with sodiumbicarbonate solution and dried over sodium sulfate. After the solventhas been distilled 01f, theresidue is distilled in vacuum. There areobtained '40 parts by Weight2,6,6-trimethylcyclohexen(l)-yl-acetaldehyde. B. P. =98 C.; n =l.480.The substance does not have any absorption maximum over 220 m in theultraviolet spectrum.

Example 2 ENOLACETATE O13 RETRODEHYDRO-Cn-ALDEHYDE A mixture of 10 partsby weight 2,6,6-trimethylcyclohexen-(Z)-ylidene-acetaldehyde, parts byvolume acetic anhydride and 01 part by weight p-toluenesulfonic acid areheated at 95 C. for 90 minutes. Thereupon it is cooled to 20 to 30 C.and poured into amixture of 20 parts by weight ice and 30 parts byvolume water. The oily reaction product is extracted withpetroleumethcr, washed with sodium bicarbonate solution and with waterand dried over sodium sulfate. After the concentration of thepetroleum-ether solution, the residue is distilled in vacuum. There areobtained 10 parts by weight 2-l2',6,6'-trimethylcyclohexadien-(1,3') yl]lacetoxy-ethylene, B. P. =1l5 C.; n =1.505; ultraviolet absorptionmaximum at 284 mu;

E=340 (in petroleum-ether solution).

B-DEI'IYDRO-Cn-ALDEHYDE To a solution of 6.8 parts by weight2-[2,6,6'-trimethylcyclohexadien-( l ,3 -yl 1 -acetoxy-ethylene in 100parts by volume ethyl alcohol there are added 10 parts by volume 20%aqueous caustic potash solution and set aside for 5 hours at 20 to 25 C.Thereupon the reaction solution is diluted with 100 parts by volume ofwater and slightly acidified With 10% sulfuric acid. The reactionproduct is extracted with petroleum-ether, washed with water and driedover sodium sulfate, and the solvent 7 is evaporated. The residue isdistilled in vacuum and there are obtained 49 parts by weight2,6,6-trimethylcyclohexadien-(1,3)-yl-acetaldehyde, B. P. C.; Ht 267 mu;

n =l.499; ultraviolet absorption maximum E} 3 15 (in. petroleum-ethersolution) Example 3 "'ENOLACETATE OF ISO-Cn-ALDEHYDE 9 parts by weight4-[2',6',6'-trimethylcyclohexylidene]- 2-methyl-buten-(2)-al-( 1) areheated with 6.5 parts by volume isopropenylacetate and 0.045 part byWeight ptoluenesulfonic acid for 3 hours at 110 to C., the acetoneproduced being sloWl-y distilled otf from the reaction-mixture. Aftercooling, the reaction solution is poured into a mixture of 10 parts byweight of ice and 10 parts by volume of water. The reaction product isextracted with petroleum-ether, the petroleum-ether solution is washedwith sodium bicarbonate solution and with water and dried over sodiumsulfate. After the solvent has been distilled off, there are obtained10.4 parts by weight of crude 4-[2',6,6-trimethylcyclohexen-(l')-yl]-Z-methyl-I acetoXy-butadiene-( 1,3), which is sufficiently pure for thefurther treatment. By distillation in vacuum, there can be obtained acolorless product; B. P. =ll0 C.;'n =1.522; ultraviolet absorptionmaximum at 264 m Ei=690 (in petroleum-ether solution).

B-Cu-ALDEHYDE 10.4 parts'by weight 4-[2Z6?,6'-trimethylcyclohexen-1')-y1] -2-methyl-l-acetoxy-butadiene-( 1,3) are saponificd, asindicated in Example 2, with 100 parts by volume of ethyl alcohol and 13parts by volume of 20% aqueous caustic potash solution and worked up.Upon distillation in a high vacuum there are obtained 7.5 parts byweight of 4- [2',6',6-trimethylcyclohexen-( l)-yl] -2-tnethylbuten-(2)-al-(l); B. P. =86 C.; n =l.509; ultraviolet absorption maximumat 226 ru (in petroleum-ether solution).

Example 4 B-DEHYDRO-Cu-ALDEHXDE 136 .parts by Weight4-[2,6',6-trirnethylcyclohexen- (2)-ylidene]-2-methyl-buten-(2)-al-(l)are heated with 97 parts by volume isopropenyl acetate and 0.7 parts byweight p-toluenesulfonic acid for 3 to 4 hours at 100 to 140 C. whilepassing through a weak stream of nitrogen, the acetone released beingcontinuously distilled out of the reaction mixture. Thereupon it isallowed 'to cool. The crude 4-[2,6,6'-trimethylcyclohexadien-(l',3)-yl]-2-methy1-1-acetoxy-butadiene-(1,3), thus obtained is directlyhydrolyzed. For this purpose there are added 650 parts 'by volume methylalcohol, 65 parts by volume water and 46 parts by weight sodiumbicarbonate and the mixture is boiled while agitating for 12 hours underreflux. his then poured onto 2000 parts by volume of icewater, andslightly acidified with dilute sulfuric acid. The reaction product isextracted with petroleum-ether, Washed with sodium bicarbonate solutionand dried over sodium sulfate. After the solvent has been evaporated,the residue is distilled in a high vacuum. There are obtained 98 partsby weight 4-[2,6',6'-trimethylcyclohexadien-(1,3')-yll-2-methyl'buten-(2)-al-(1); B. P. 5=80 C.; n '=1.530; ultraviolet absorptionmaxima at 224 and'268 my;

l=795 and 345 (in petroleum-ether solution).

We claim:

1. A process which comprises reacting a member of the group' consistingof 2,6,6-trimethylcyclohexylidenea'cetaldehyde,2,6,6-trimethylcyclohexen-(2)-ylidene-acetaldehyde, 4-[2,6',6trimethylcyclohexylidene] 2-met hyl buten (2) al (1) and4-[2',6',6'-trimethylcyclohexen-( 2)-ylidene]-2-methyl-buten-( 2 -al-(lwith a member of the group consisting of lower aliphatic carboxylic acidanhydride and enol ester of a'ketone having a lower boiling point thanthe starting aldehyde in the presence of an acid condensation agent toproduce, respectively, a member of the group consisting of 2 [2,6',6trimethylcyclohexen (1) yl] 1- acyloxy ethylene, 2 [2,6,6'trimethylcyclohexadien (1,3) yl] 1 acyioxy ethylene, 4 [2',6,6'-trirnethylcyclohexen (1) yl] 2 methyl 1 acyloxy-butadiene (1,3) and 4[2,6,6-trimethylcyclohexadien (1',3) yl] 2 methyl 1 acyloxybutadiene-(1,3) and hydrolyzing the enol esters thus obtained under mildconditions in aqueous medium to produce, respectively, a member of thegroup consisting of 2,6,6- trimethylcyclohexene (1) yl acetaldehyde,2,6,6- trimethylcyclohexadien (1,3) yl acetaldehyde, 4- [2,6,6trimethylcyclohexene (1) yl] 2 methylbuten (2) al (1) and 4 [2,6,6'trimethylcyclohexadien (1,3) yl] 2 methyl buten (2) al (1).

2. A process as in claim 1 wherein the enol ester is isopropenylacetateand the acid condensation agent is p-toluene-sulfonic acid.

3. A process as in claim 1 wherein the anhydride is acetic anhydride andthe acid condensation agent is sodium acetate.

4. A process which comprises hydrolyzing 2-[2,6',6-trimethylcyclohexen-(l')-yl]-l-acyloxy-ethylene in aqueous medium undermild conditions to produce 2,6,6-trimethylcyclohexen-( 1-ylacetaldehyde.

5. A process which comprises hydrolyzing 2-[2,6',6'-trimethylcyclohexadienl ,3 -yl] -1-acyloxy-ethy1ene in aqueous mediumunder mild conditions to produce 2,6,6- trimethy1cyc1ohexadien-( 1,3-yl-acetaldehyde.

6. A process which comprises hydrolyzing 4-[2,6',6'-

trimethylcyclohexen (1) yl] 2 methyl 1 acyloxy-butadiene-( 1,3) inaqueous medium under mild conditions to produce 4 [2',6',6'trimethylcyclohexen- 1)-yl]-2-methy1-buten-(2)-al-( 1) 7. A processwhich comprises hydrolyzing 4-[2,6',6- trimethylcyclohexadien (1',3')yl] 2 methyl 1 acyloxy-butadiene-(l,3) in aqueous medium under mildconditions to produce 4 [2',6,6'-trimethylcyclohexaclien- (1,3-yl]-2-n1ethyl-buten-(2) -al-( 1 8. A compound of the group consistingof 4-[2,6',6- trimethylcyclohexen (1) yl] 2 methyl 1 loweralkanoyloxybutadiene (1,3) and 4 [2,6',6' trimethylcyclohexadien (1,3')yl] 2 methyl 1 lower alkanoyloxy-butadiene-( 1,3

9. 4 [2,6,6' trimethylcyclohexen (1') yl] 2- methyll-lo-weralkanoyloxy-butadiene-( 1,3)

10. 4 [2,6',6' trimethylcyclohexadien (1',3')- yl] -2-methyl-1-lowera1kanoyloxy-butadiene-( 1,3)

11. 4 [2',6,6 trimethylcyclohexen (1') yl]-2-methyl-1-acetoxy-butadiene-( 1,3

12. 4 [2,6,6 trimethylcyclohexadien (1',3)- yl]-2-methyl-1-acetoxy-butadiene-( 1,3

References Cited in the file of this patent UNITED STATES PATENTS2,466,737 Quattlebaum et al Apr. 12, 1949 FOREIGN PATENTS 638,940Germany Nov. 25, 1936 OTHER REFERENCES Karrer et al.: Helv. Chim. Acta34, 1408-11 (1951).

1. A PROCESS WHICH COMPRISES REACTING A MEMBER OF THE GROUP CONSISTINGOF 2,6,6-TRIMETHYLCYLOHEXYLIDENEACETALDEHYDE,2,6,6-TREIMETHYLCYCLOHEXEN-(2)-YLIDENE-ACETALDEHYDE, 4-(2'',6'',6-TRIMETHYLCYCLOHEXYLIDENE) - 2 METHYL- BUTEN - (2) - AL (1) AND4-(2'',6'',6''-TRIMETHYLCYCLOHEXEN-(2)-YLIDENE)-2-METHYL-BUTEN-(2)-AL-(1)WITH A MEMBER OF THE GROUP CONSISTING OF LOWER ALIPHATIC CARBOXYLIC ACIDANHYDRIDE AND ENOL ESTER OF A KETONE HAVING A LOWER BOILING POINT THANTHE STARTING ALDEHYDE IN THE PRESENCE OF AN ACID CONDENSATION AGENT TOPRODUCE, RESPECTIVELY, A MEMBER OF THE GROUP CONSISTING OF 2 -(2'',6'',6'' - TRIMETHYLCYCLOHEXEN - (1'') YLL - 1ACYLOXY - ETHYLENE,2 - (2'',6'',6'' - TRIMETHYLCLOHEXADIEN - (1'',3'') -Y1) -1- ACYLOXY -ETHYLENE, 4 - (2'',6'',6''TRIMETHYLCYCLOHEXEN - (1'') - Y1) - 2 -ACYLOXY-BUTADIENE - (1,3) AND 4 - (2'',6'',6''-TRIMETHYLCYLOHEXADIEN -(1'',3'') - Y1) - 2 - METHYL - 1 - ACYLOXY - BUTADIENE- (1,3) ANDHYDROLYZING THE ENOL ESTER THUS OBTAINED UNDER MILD CONDITIONS INAQUEOUS MEDIUM TO PRODUCE, RESPECTIVELY, A MEMBER OF THE GROUPCONSISTING OF 2,6,6TRIMETHYLCYCLOHEXENE - (1) - YL - ACETALDEHYDE, 4TRIMETHYLCYCLOHEXADIEN - (1,3) - YL - ACETALDEHYDE, 4(2'',6'',6''-TRIMETHYLCYCLOHEXEND - (1'') -YL) - 2 - METHYLBUTEN - (2)AL - (1) AND 4 - (2'',6'',6''- TRIMETHYLCYCLOHEXADIEN- (1,3'') - YL) -2 - METHYL - BUTEN - (2) AL - (1).